Solvent Influence on Cellulose 1,4‐β‐Glycosidic Bond Cleavage: A Molecular Dynamics and Metadynamics Study

We explore the influence of two solvents, namely water and the ionic liquid 1‐ethyl‐3‐methylimidazolium acetate (EmimAc), on the conformations of two cellulose models (cellobiose and a chain of 40 glucose units) and the solvent impact on glycosidic bond cleavage by acid hydrolysis by using molecular dynamics and metadynamics simulations. We investigate the rotation around the glycosidic bond and ring puckering, as well as the anomeric effect and hydrogen bonds, in order to gauge the effect on the hydrolysis mechanism. We find that EmimAc eases hydrolysis through stronger solvent–cellulose interactions, which break structural and electronic barriers to hydrolysis. Our results indicate that hydrolysis in cellulose chains should start from the ends and not in the centre of the chain, which is less accessible to solvent.     

Structural and electronic comparative analysis of aminopyridazines showing anti-GABA activity. Crystal structure of 2-(carboxy-3′-propyl)-3-amino-6-cyclohexylpyridazinium bromide.Ab initio Mulliken population analysis of the 6-phenyl-substituted analog compared to GABA

The crystal structure of 2-(carboxy-3-propyl)-3-amino-6-cyclohexylpyridazinium bromide has been determined by single-crystal X-ray diffraction techniques and refined by full-matrix least squares. The compound crystallized in the tri-clinic space groupP ¯1 witha=10.275(1),b=11.215(1),c=7.082(1) Å,=91.84(1),=102.21(1), =106.77(1)°, andZ=2. FinalR-factor is 0.045. The main structural results are very similar to the ones observed for the 6-phenyl analog. These two compounds are GABA-A antagonists.Ab initio molecular orbital calculations, with STO-3G and 4-31G basis sets, suggest that the exocyclic nitrogen accurately mimics the nitrogen atom of GABA.     

Comparison of 17beta-estradiol structures from x-ray diffraction and solution NMR

The NMR-derived structure of estrogen (17beta-estradiol, E2), the drug of choice for postmenopausal women, was compared with a recent literature crystal x-ray structure of Fab-bound E2. 1H and 13C NMR spectra of E2 were acquired in DMSO-d6. Assignments were obtained from an analysis of DQF-COSY, TOCSY, HETCOR, HMQC and HMBC 2D NMR spectra. The 1H and 13C NMR assignments are the first reported for E2 in DMSO-d6. Two solution structures, S1 and S2, were obtained with molecular modeling using NOE constraints. S1 overlaps with the crystal structure for all rings. S2 shows prominent differences in the C-ring (C9--C11--C12--C13) segment, which deviates from a chair conformation, and excellent overlap in the A-, B- and D-rings of E2. The C-ring in S2 adopts a boat conformation as opposed to a chair conformation in the x-ray and S1 structures. The S2 structure is about 6 degrees more twisted than the bound x-ray and S1 models. The S1, S2 and x-ray structures had ring bowing values of 10.1 +/- 0.3, 11 +/- 1 and 10.37 degrees , respectively. Of the 100 solution conformers generated, 83 had S1 conformation and 17 had S2 conformation, with average internal energies of 112 +/- 2 and 141 +/- 2 kcal mol(-1), respectively. The 100 S1- and S2- derived conformers showed a r.m.s.d. of 0.72 A for all atoms. The x-ray, S1 and S2 C18--O17 distances were 2.93, 2.92 +/- 0.01 and 2.93 +/- 0.01 A, respectively, and the O3--O17 distances were 11.06, 11.18 +/- 0.12, and 10.89 +/- 0.05 A, respectively.     

Intrinsic and Intramolecular Lipophilicity Effects in O-Glucuronides

In this study, we compared the lipophilicity of O-glucuronides and their aglycones. Distribution coefficients (log D) and P values of neutral species (log P) were determined by centrifugal partition chromatography (CPC) in octanol/buffer systems. Two-phase potentiometry was also used to measure the log P value of some lipophilic solutes. The experimentally determined global influence of glucuronidation on lipophilicity, obtained as the difference (decrement) log P_{(glucuronide)} ? log P_(aglycone), was found to be ?1.30 ± 0.16 (n = 4) for glucuronides of alcohols (methyl, menthyl, neomenthyl, and chloramphenicol O-glucuronide). The mean decrement was ?2.06 ± 0.31 (n = 9) for glucuronides of phenols (phenyl, p-nitrophenyl, 1-naphthyl, 6-bromo-2-naphthyl, 4-methylumbelliferyl, 3-coumarinyl, phenolphthalein, 4′-benzophenonyl O-glucuronide, and diflunisal phenolic glucuronide). For the acylglucuronide of diflunisal and its rearrangement isomers, the mean decrement was ?1.80 ± 0.08 (n = 4; range ?1.7 to ?1.9). Differences in through-bond proximity effects as parametrized in the CLOGP algorithm seem to account for much of this difference. Conformational factors may also play a role, although it appears modest and unassessable for the glucuronides investigated here. The results imply that in vivo glucuronidation should have a stronger influence on the excretion of phenols than on that of alcohols.     

Separation strategy for acidic chiral pharmaceuticals with capillary electrochromatography on polysaccharide stationary phases

The effect of five factors on the capillary electrochromatographic enantioseparation of acidic compounds was studied using an experimental design. The studied factors were pH, acetonitrile content in the mobile phase, temperature, buffer concentration, and applied voltage. These experiments allowed defining a generic separation strategy applicable on acidic compounds with chemical and structural diversity. The starting screening conditions consist of a 45 mM ammonium formate electrolyte at pH 2.9 mixed with 65% acetonitrile, an applied voltage of 15 kV, and a temperature of 25 degrees C. The screening phase occasionally can be followed by an optimization procedure. Evaluation of the proposed strategy pointed out that it allows achieving baseline resolution within a relatively short time when a beginning of separation is obtained at the starting conditions. This strategy revealed enantioselectivity for 11 compounds out of 15, of which 10 could be baseline-separated after the proposed optimization steps.     

Rhodium(II)-Catalyzed CH Insertions with {[(4-Nitrophenyl)sulfonyl]imino}phenyl-λ3-iodane

The [Rh₂(OAc)₄]-catalyzed decomposition of {[(4-nitrophenyl)sulfonyl]imino}phenyl-λ³-iodane (NsN?IPh) resulted in formal insertions into CH bonds, activated by phenyl or vinyl groups, or by O-substituents. Scope and limitations of the reaction were investigated. Yields of up to 84% were achieved in the most favorable cases. Yields were enhanced by electron-releasing substituents and decreased by steric hindrance. Aziridination competed with allylic insertion with olefinic substrates. The insertion reaction proceeded with retention of configuration. With chiral Rh^II catalysts, a modest asymmetric induction was observed. A mechanism involving direct insertion by a Rh-complexed nitrene into the CH bond is proposed.     

Minimal number of chromatographic test parameters for the characterisation of reversed-phase liquid chromatographic stationary phases

This paper focuses on the classification or differentiation of RP-HPLC columns based on measured chromatographic properties. A chemometric study has been conducted on a published data set consisting of 85 RP-HPLC columns and on a data set consisting of 47 self-tested columns. Principal component analysis enables determination of the number of parameters necessary for a rational differentiation. The results show that reducing the number of parameters for such differentiation still allows classification of the columns just as a higher number did. It is shown that three test parameters produce a classification similar to that obtained with five parameters.     

Configuration-Odor Relationships in 5β-Ambrox

The four possible A/B cis-fused diastereoisomers of Ambrox® have been synthesized and their configurations and conformations established by X-ray and NMR analysis. Only 5β-ambrox (= 1,2,3a,4,5,5β,6,7,8,9,9a,9bα-dodecahydro-3aβ,6,6,9aβ-tetramethylnaphtho[2,1-b]furan; 5 ) has an odor quality comparable to Ambrox®. The 1,3-synperiplanar/diaxial conformation of the substituents at C(8) ( = C(3a)) and C(10) (= C(9a)) has thus been confirmed to be a compulsory structure element for the particular odor.     

Influence of peak measurement parameters on the quality of chiral electrophoretic separations

The effect of nine peak measurement/analysis parameters on chiral capillary electrophoresis (CE), followed by UV detection, was studied. The parameters pertained UV-detection (detection wavelength, reference wavelength, and wavelength bandwidths), signal processing (data acquisition rate, type and amount of filtering) and peak detection (detection threshold and peak width). The influence of these factors on the chiral separation of dimethindene enantiomers was studied at two different concentrations (i.e., at high and low signal-to-noise (S/N) ratio) by the means of experimental designs. The electropherogram characteristics considered were the resolution between the two enantiomers, the peak areas, and the S/N ratio. A D-optimal design was first used as screening design to identify the most critical parameters. Afterwards, a modelling of the different responses as a function of these critical parameters was performed based on the results of a face-centered central composite design. The results showed that the signal-processing parameters should be carefully selected when developing a CE separation since very important variations in the separation, the S/N ratio and the peak area of the substances can occur by setting these parameters at different levels. The detection wavelength should also be carefully chosen for optimal peak area measurement. The role of these parameters becomes more important with decreasing concentration of the analytes (i.e., low S/N ratio). This study showed that the peak measurement/analysis parameters should be optimized as the chemical and physical parameters of a method. They also should always be well specified in order to allow a good transfer of a method from one instrument to another.